METHODS

Allocation: Allocation concealed: Infants were electronically randomised during the first 24 hours of life to either receive i.v. hydrocortisone or placebo in a 1:1 ratio. The study drug and placebo had identical appearance and the content was masked to investigator staff and parents.

Blinding:Parents, medical and nursing staff as well researchers and analysts were all blinded.

Follow-up period: From birth to 36 weeks of postmenstrual age. Follow up of the study groups to establish neurodevelopmental outcome at corrected age of 18-22 month is currently in progress.

Inclusion criteria: all inborn neonates between 24+0 and 27+6 weeks gestation admitted to one of the 21 participating tertiary-level NICU’s between May 25th and January 31st 2014.

Exclusion criteria: rupture of membranes before 22 weeks of gestation, birth weight less than the third percentile for gestational age, severe perinatal asphyxia, antenatally diagnosed congenital malformations, known chromosomal aberrations or infants who were expected to die shortly after birth for any other reason.

Intervention: Intravenous administration of hydrocortisone to extremely preterm infants, starting in the first 24hours of postnatal life and continuing for 7 days at a dose of 1mg/kg divided in 2 doses /day, followed by administration of half the total daily dose once a day for three more days. The intervention was controlled with a placebo group at a 1:1 ratio.

Secondary outcomes: BPD at 36 weeks of postmenstrual age, death, surgical ligation of patent ductus arteriosus, ability to wean from any ventilator support and supplemental oxygen at 36 weeks of postmenstrual age.

Analysis and Sample Size: A sample size calculation was performed using a type I error rate of 5% at a power of 80%. The sample size was 786 infants. A sequential analytical design was used based on intention-to-treat analysis in order to avoid prolonging the trial after either efficacy or futility had been established. An interim analysis was performed every time an additional 100 patients reached the primary outcome (survival without BPD at 36 weeks of postmenstrual age). Due to financial and technical limitations the trial was stopped at the fourth interim analysis when a total of 521 have been included into the study.

For secondary outcomes, initially logistic regression analysis was used followed by cumulative curves to describe the incidence of various events, and a Fine and Gray model to examine the effect of treatment related to competing risk factors.

Patient follow-up: Initially 1072 neonates were screened. Of those 123 have been excluded because of poor short-term prognosis, receiving medications or not compatible with the study protocol or were already enrolled in another study. From the remaining 949 patients 426 did not undergo randomization due to lack of consent. From the remaining 523 randomly assigned patients 256 were assigned to receive hydrocortisone and 267 to receive placebo. The final number of patients participating was diminished by one in each arm because parents withdrew consent.

MAIN RESULTS

Survival without BPD at 36 weeks of postmenstrual age was significantly higher in the group of infants treated with hydrocortisone than in controls. The two components of the primary outcome, death and BPD separately were not different between the two groups. The post-hoc analysis showed a significant sex difference indicating a greater benefit for the females treated with hydrocortisone. The secondary outcomes, number of extubated patients on day 10, weaning from supplemental oxygen at 36 weeks of postmenstrual age and the need for PDA ligation were significantly in favor for the hydrocortisone treated group. Only weaning from ventilator support at 36 weeks of postmenstrual age was not significantly different between the two groups. With regards to the adverse events – in particular gastrointestinal perforation, NEC, insulin requirements and late onset-sepsis – no significant differences could be shown between the two treatment arms. Neither was there a difference between the groups for air leaks, pulmonary haemorrhage, severe IVH, cystic PVL, ROP or death before discharge.

Data are n (%) or n/N (%). *ORs were adjusted for gestational age group

CONCLUSION

Baud et al. concludes that treatment with low dose hydrocortisone for 10 days started within the first 24 hours of life has a significant beneficial effect on BPD free survival in infants born before 28 weeks of gestation. The treatment was also associated with reduced need for patent ductus arteriosus ligation and early extubation. For the observed study period, up to 36 weeks of post menstrual age, the treatment seemed to be safe.

COMMENTARY

Olivier Baud and colleagues investigated in a large RCT the effect of a ten-day course of low dose prophylactic hydrocortisone given to extremely preterm infants born between 24 and 27 weeks of gestational age. Survival without bronchopulmonary dysplasia (BPD) was significantly higher in the group of infants receiving hydrocortisone than in controls receiving placebo. This effect was most pronounced in females and in infants exposed to chorioamnionitis before birth. For the secondary outcomes, the treatment group exhibited lower odds for PDA ligation, higher numbers of patients extubated on day 10 and higher proportion of patients weaned from any supplemental oxygen at 36 weeks of postmenstrual age.

Despite recommendations against the use of postnatal steroids because of adverse long term neurodevelopmental outcomes neonatologists across the world use these drugs in order to treat BPD 1. The fact that ELBW infants can suffer from adrenal insufficiency, particular the sickest ones, has been shown earlier and might make early supplementation reasonable2. Furthermore, the connection between low cortisol levels and early inflammation promoting the development of bronchopulmonary dysplasia from early on has been described previously and potentially justifies the treatment with steroids 3.

This well designed trial is one of the largest on this subject and provides us with important information on short term outcome as well as on the safety of hydrocortisone treatment. It seems promising that even the lowest dose ever tested had a beneficial effect on primary outcome of survival without BPD. This trial also gives assurance with the regard to the feared side effect of gastrointestinal perforation and very fortunately even the two year follow up data are available and giving reassurance with regard to neurodevelopmental outcome4,5. Caution is warranted with regards to the higher incidence of late-onset-sepsis in the treatment group. Although not statistical significant a six percent difference between the groups might be of clinical interest.

Treatment with postnatal steroids in order to prevent BPD seems to be a hot topic. The recent trial by Bassler et al. and the updated Cochrane review are suggesting a benefit for using early inhaled steroids in extreme preterm infants6,7. However, the long term risk/benefit ratio for treatment with steroids still needs to be identified for either application way even beyond the two year data currently available for this trial. A weakness might be the fact that the study was discontinued prior to targeted sample size of 786 infants. Nevertheless, the sequential analytical design allowed appropriate analysis after the fourth interim analysis anyway.

Neonatologists around the world are faced with an increasingly immature population consequently leading to a higher prevalence of BPD which makes prevention and treatment strategies inevitable. Early supplementation with hydrocortisone as described in this trial might be a promising way forward. The question whether this treatment strategy could be particularly beneficial in infants not exposed to antenatal steroids has not been addressed here. Further studies on this subject focusing on type of steroid, timing of treatment, dosage and duration of treatment are needed.